Substituted pyrazolopyrimidines and method of use

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , L 1 and G 1 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by positive allosteric modulation of the γ-aminobutyric acid B (GABA-B) receptor. Methods for making the compounds are described. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

What is claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or isotopically labeled form thereof, wherein: 
         R 1  is selected from the group consisting of C 1 -C 6 alkyl,C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkylC 1 -C 6 alkyl, wherein
 the C 1 -C 6 alkyl and the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1a  independently selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylsulfonylamino, amido, carboxy, cyano, halogen, hydroxy, and oxo; and 
 the C 3 -C 6 cycloalkyl and the C 3 -C 6 cycloalkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1b  independently selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkyl, amido, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylsulfonylamino, carboxy, cyano, halogen, haloC 1 -C 6 alkyl, hydroxy, hydroxyC 1 -C 6 alkyl, and oxo; 
 
         R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl; or 
         R 1 , R 2  and the nitrogen to which they are attached form a saturated 4-7-membered N-bound heterocycle, which in addition to the nitrogen atom may have one further heteroatom selected from O, S and N as a ring member, wherein:
 each such 4-7-membered heterocycle is unsubstituted or substituted with one or more identical or different substituents R 1c , where R 1c  is selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylsulfonylamino, amido, carboxy, cyano, halogen, haloC 1 -C 6 alkyl, amino, hydroxy, hydroxyC 1 -C 6 alkyl, oxo, spirocyclic bound C 3 -C 6 cycloalkyl; and spirocyclic bound saturated 4-6-membered heterocycle; wherein
 each spirocyclic bound C 3 -C 6 cycloalkyl and spirocyclic bound 4-6-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, cyano, halogen, haloC 1 -C 6 alkyl, hydroxy, and hydroxyC 1 -C 6 alkyl; 
 
 
         R 3  is hydrogen; 
         R 4  is C 1 -C 6 alkyl; 
         L 1  is (CR 5 R 6 ) m , wherein m is 1 and
 R 5  and R 6 , are, at each occurrence, independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; 
 and 
 
         G 1  is selected from the group consisting of C 5 -C 10 cycloalkyl, 5-6-membered heteroaryl, and phenyl; wherein
 each C 5 -C 10 cycloalkyl, 5-6-membered heteroaryl, and phenyl is unsubstituted or substituted with one or more identical or different substituents R G , where R G  is selected from the group consisting of C 1 -C 6 alkyl, cyano, haloC 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy and haloC 1 -C 6 alkoxy. 
 
       
     
     
       2. The compound or pharmaceutically acceptable salt of  claim 1  wherein R 5  is hydrogen and R 6  is C 1 -C 6 alkyl. 
     
     
       3. The compound or pharmaceutically acceptable salt of  claim 1 , wherein
 G 1  is selected from the group consisting of 5-6-membered heteroaryl and phenyl; wherein the 5-6-membered heteroaryl and phenyl are unsubstituted or carry 1, 2, 3 or 4 radicals R G . 
 
     
     
       4. The compound or pharmaceutically acceptable salt of  claim 1 , wherein
 G 1  is selected from the group consisting of phenyl, 3-chlorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, pyridine-2-yl and 5-chloropyridin-2-yl. 
 
     
     
       5. The compound or pharmaceutically acceptable salt of  claim 1 , wherein:
 R 1  is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkylC 1 -C 6 alkyl, wherein
 the C 1 -C 6 alkyl and the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1a ; and 
 the C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl, 4-7-membered heterocycle are unsubstituted or substituted with one or more substituents R 1b ; and 
 
 R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl. 
 
     
     
       6. The compound or pharmaceutically acceptable salt of  claim 5 , wherein:
 R 1  is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted with one or more halogen atoms; and 
 R 2  is hydrogen. 
 
     
     
       7. The compound or pharmaceutically acceptable salt of  claim 5 , wherein:
 R 1  is selected from the group consisting of C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkylC 1 -C 6 alkyl, wherein
 the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl is unsubstituted or substituted with one or more substituents R 1a , and 
 the C 3 -C 6 cycloalkyl and the C 3 -C 6 cycloalkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1b ; and 
 
 R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl. 
 
     
     
       8. The compound or pharmaceutically acceptable salt of  claim 1 , wherein:
 R 1 , R 2  and the nitrogen to which they are attached form a 4-7-membered heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl wherein azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl are unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c . 
 
     
     
       9. The compound or pharmaceutically acceptable salt of  claim 8 , wherein:
 R 1 , R 2  and the nitrogen to which they are attached form a 4-5-membered heterocycle selected from the group consisting of azetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c . 
 
     
     
       10. The compound or pharmaceutically acceptable salt of  claim 8 , wherein:
 R 1 , R 2  and the nitrogen to which they are attached form a 6-7-membered heterocycle selected from the group consisting of piperidinyl, piperazinyl, and azepanyl wherein piperidinyl, piperazinyl, and azepanyl are unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c . 
 
     
     
       11. The compound or pharmaceutically acceptable salt of  claim 1 , wherein the moiety NR 1 R 2  is selected from the group consisting of azetidin-1-yl, 3-ethyl-2-carboxylazetidin-1-yl, pyrroldin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-(acetylamino)pyrrolidin-1-yl, 3-(methylsulfonylamino)pyrrolidin-1-yl, 3-aminocarbonylpyrrolidin-1-yl, piperidin-1-yl, 3-fluoropiperidin-1-yl, 4-fluoropiperidin-1-yl, 2-(2-hydroxyethyl)piperidin-1-yl, 2-ethylpiperidin-1-yl, 2-(hydroxymethyl)piperidin-1-yl, 3-(hydroxymethyl)piperidin-1-yl, 2-oxopiperidin-1-yl, 3-(methylsulfonylamino)piperidin-1-yl, 2-(2-hydroxyethyl)-3-oxopiperazin-1-yl, 3,3-difluorpiperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxy-3,3-difluoropiperidin-1-yl, 2,2,2-trifluoroethylamino, tert-butylamino, 1-(trifluoromethyl)-ethylamino, 1-methylcyclopropylamino, 1-(trifluoromethyl)cyclopropylamino, 3-fluorocyclobutylamino, 3,3-difluorocyclobutylamino, 3-hydroxycyclobutylamino, (3,3-difluorocyclobutyl)methylamino, 2-oxa-6-azaspiro[3.4]oct-6-yl, 2-oxa-7-azaspiro-[3.5]non-7-yl, 7-oxa-2-azaspiro[3.5]non-2-yl and 3-hydroxy-7-azaspiro[3.4]oct-7-yl. 
     
     
       12. A compound, selected from the group consisting of:
 2-{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol; 
 {1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}methanol; 
 2-(4-chlorobenzyl)-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine; 
 2-(4-chlorobenzyl)-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-3,3-difluoropiperidin-4-ol; 
 (3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol; 
 (3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-ol; 
 {(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol; 
 2-(4-chlorobenzyl)-5-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine; 
 1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-one; 
 N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide; 
 2-(4-chlorobenzyl)-5-methyl-7-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine; 
 7-(azetidin-1-yl)-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 N-tert-butyl-2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 2-(4-chlorobenzyl)-5-methyl-N-[1-(trifluoromethyl)cyclopropyl]pyrazolo[1,5-a]pyrimidin-7-amine; 
 2-(4-chlorobenzyl)-5-methyl-N-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrimidin-7-amine; 
 N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}acetamide; 
 2-(4-chlorobenzyl)-5-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine; 
 1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxamide; 
 2-(4-chlorobenzyl)-5-methyl-N-[(2R)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidin-7-amine; 
 {(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanol; 
 2-(1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol; 
 2-[1-(4-chlorophenyl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine; 
 2-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 2-[1-(4-chlorophenyl)ethyl]-7-(4-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 (1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)methanol; 
 2-[1-(4-chlorophenyl)ethyl]-7-(3-fluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 2-[1-(4-chlorophenyl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 N-tert-butyl-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 2-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrazolo[1,5-a]pyrimidine; 
 (3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol; 
 (3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol; 
 7-(azetidin-1-yl)-2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine; 
 2-[1-(4-chlorophenyl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine; 
 2-[1-(4-chlorophenyl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 (2R,3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-3-ethylazetidine-2-carboxylic acid; 
 2-[1-(4-chlorophenyl)ethyl]-N-[(3,3-difluorocyclobutyl)methyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 N-[(3S)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide; 
 cis-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol; 
 trans-3-({2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclobutanol; 
 6-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}-6-azaspiro[3.4]octan-1-ol; 
 2-[1-(4-chlorophenyl)ethyl]-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 2-[1-(4-chlorophenyl)ethyl]-7-[(2R)-2-ethylpiperidin-1-yl]-5-methylpyrazolo[1,5-a]pyrimidine; 
 N-[(3R)-1-{2-[1-(4-chlorophenyl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide; 
 2-(1-{2-[1-(4-chlorophenyl)propyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol; 
 2-[1-(4-chlorophenyl)propyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 2-(1-{2-[1-(4-chlorophenyl)-2-methylpropyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol; 
 2-[1-(4-chlorophenyl)-2-methylpropyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 2-(1-{2-[1-(4-chlorophenyl)butyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol; 
 2-[1-(4-chlorophenyl)butyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 2-(1-{5-methyl-2-[3-(trifluoromethyl)benzyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidin-2-yl)ethanol; 
 2-{1-[5-methyl-2-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol; 
 (2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxamide; 
 2-[1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]ethanol; 
 5-methyl-7-(2-oxa-6-azaspiro[3.4]oct-6-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine; 
 5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine; 
 (3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-3-ol; 
 N-(3-fluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine; 
 N-[(3S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide; 
 5-methyl-N-(1-methylcyclopropyl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine; 
 [1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-yl]methanol; 
 (2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxylic acid; 
 7-(4-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine; 
 7-(3-fluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine; 
 3-(2-hydroxyethyl)-4-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperazin-2-one; 
 N-[(3,3-difluorocyclobutyl)methyl]-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine; 
 7-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine; 
 N-[(3R)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl]acetamide; 
 7-(3,3-difluoropiperidin-1-yl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine; 
 1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-2-one; 
 N-tert-butyl-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine; 
 N-(3,3-difluorocyclobutyl)-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine; 
 5-methyl-7-(2-oxa-7-azaspiro[3.5]non-7-yl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine; 
 1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidine-3-carboxamide; 
 (1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-yl)methanol; 
 2-[1-(5-chloropyridin-2-yl)ethyl]-N-(3,3-difluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 (3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}piperidin-3-ol; 
 2-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 2-[1-(5-chloropyridin-2-yl)ethyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine; 
 N-tert-butyl-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 2-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine; 
 2-[1-(5-chloropyridin-2-yl)ethyl]-N-(3-fluorocyclobutyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-amine; 
 2-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)pyrazolo[1,5-a]pyrimidine; 
 N-[(3R)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide; 
 N-[(3S)-1-{2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidin-7-yl}pyrrolidin-3-yl]acetamide; 
 N-{(3R)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]pyrrolidin-3-yl}methanesulfonamide; 
 N-{(3S)-1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-3-yl}methanesulfonamide; and 
 2-{1-[2-(3-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol, or a pharmaceutically acceptable salt thereof. 
 
     
     
       13. A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt of  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
       14. The compound of pharmaceutically acceptable salt of  claim 1 , wherein:
 R 1  is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkylC 1 -C 6 alkyl; wherein 
 the C 1 -C 6 alkyl and the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1a  independently selected from the group consisting of cyano and halogen; and 
 the C 3 -C 6 cycloalkyl and the C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1b  independently selected from the group consisting of C 1 -C 6 , cyano, halogen and haloC 1 -C 6 alkyl; 
 R 2  is hydrogen; or 
 R 1 , R 2  and the nitrogen to which they are attached from a saturated 4-6-membered N-bound heterocycle, which in addition to the nitrogen atom may have one further heteroatom selected from O and N as a ring member, wherein:
 each such 4-6-membered heterocycle is unsubstituted or substituted with one or more identical or different substituents R 1c , where R 1c  is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylsulfonylamino, amido, carboxy, cyano, halogen, haloC 1 -C 6 alkyl, hydroxy, hydroxyC 1 -C 6 alkyl, oxo, spirocyclic bound C 3 -C 6 cycloalkyl; and 
 spirocyclic bound saturated 4-6-membered heterocycle; wherein
 each spirocyclic bound C 3 -C 6 cycloalkyl and spirocyclic bound 4-6-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and hydroxyC 1 -C 6 alkyl; and 
 
 
 G 1  is selected from the group consisting of C 5 -C 10 cycloalkyl, 5-6-membered heteroaryl, and phenyl; wherein
 each C 5 -C 10 cycloalkyl, 5-6 -membered heteroaryl, and phenyl is unsubstituted or substituted with one or more identical or different substituents R G , where R G  is selected from the group consisting of C 1 -C 6 alkyl, cyano, haloC 1 -C 6 alkyl and halogen.